PROJECT SUMMARY/ABSTRACT This application for a Mid-Career Investigator Award (K24) will advance the capacity of the candidate, Dr. Adam Leventhal, to operate a productive program of mentoring and science dedicated to tobacco use treatment patient oriented research (POR) with vulnerable populations, including individuals with behavioral health comorbidities and other disadvantaged groups. Dr. Leventhal will engage in his own training and career development activities that will improve his scientific skills and ability to mentor by completing coursework, attending workshops, and interacting with an outstanding group of expert clinical scientist collaborators. Planned activities will optimize success in his training goals of increasing knowledge and skills in the areas of tobacco use treatment-outcome: (1) clinical trial protocol design and implementation (i.e., recruiting, retaining, following, treating, and assessing treatment-seeking patients) with an emphasis on vulnerable populations, (2) advanced data analysis, (3) clinical trial design methodologies, and (4) mentoring. The proposed research projects will position Dr. Leventhal and his trainees to leverage existing strengths in patient-oriented research on the mechanisms underlying tobacco use and translate this research program to clinical treatment outcome trials in the form of: (Aim 1) A new pilot clinical trial testing high-dose bupropion for smokers with anhedonia-related psychopathology, (Aim 2) A new analysis of existing data from an ongoing smoking cessation trial testing varenicline + naltrexone combination therapy in heavy drinking smokers, and (Aim 3) Completion and submission of other funded POR grants. The plan to advance Dr. Leventhal?s mentoring capacity will involve dedicated time and resources for recruiting and training junior faculty, post-docs, medical residents, graduate students, and undergraduate students in health behavior studies, clinical psychology, psychiatry, medicine, social work, and other fields who wish to conduct patient-oriented tobacco use research. He will provide training in the areas of clinical translational research methods, data analysis, data interpretation, manuscript preparation, grantsmanship, research ethics, and pro- fessional development. Mentoring will occur through Dr. Leventhal?s active research laboratory, which includes 4 junior faculty who each have their own external research funding, and hosts weekly individual and group meet- ings with mentees, a journal club, and an external speaker series. A new university-wide multi-school initiative to develop a collaborative Institute for Addiction Science at USC led by Dr. Leventhal will provide him additional opportunities to interact with trainees form a wide variety of clinical science disciplines across numerous depart- ments and programs. By executing the proposed activities in this Mid-Career (K24) award, Dr. Leventhal will be optimally-positioned to develop a new talented generation of patient-oriented researchers engaged in a high- impact translational treatment research program that reduces the tobacco burden in vulnerable populations.